1. Field of the Invention
The present invention relates to selective inhibition of calcium-independent myocardial phospholipase A.sub.2 (PLA.sub.2). More particularly, the present invention relates to a method of inhibiting calcium-independent myocardial PLA.sub.2, without inhibiting other calcium-dependent mammalian PLA.sub.2 enzymes, utilizing certain substituted enol lactones as selective inhibitors.
2. Background Related Art
PLA.sub.2 catalyzes the hydrolysis of the sn-2 ester group of membrane phospholipids to give a lysophospholipid and a free fatty acid, as illustrated in equation (1) for the hydrolysis of a diacylphosphatidylcholine. Evidence has accumulated for a potential role of PLA.sub.2 in myocardial injury to the ischemic heart. ##STR2##
For example, it has been shown that endogenous fatty acids increase several fold in an ischemic dog heart in vivo and in isolated perfused ischemic rat and dog hearts. See, for example, van der Vusse et al, Circ. Res. 50, 538-46 (1982); Chien et al, Circ. Res., 54, 313-22 (1984); Burton et al, Am. J. Pathol., 124, 238-45 (1985). It has also been shown that lysophospholipids accumulate 2 to 3 fold in the ischemic cat heart in vivo, Corr. et al, J. Clin. Invest., 83, 927-36 (1989). The accumulation of the products of phospholipid hydrolysis implies that a PLA.sub.2 may become activated in the ischemic heart.
Lysophospholipids have also been implicated as potential mediators of sudden cardiac death, Corr et al, "Lethal Arrhythmias Resulting from Myocardial Ischemia and Infarction", Rosen & Patti, eds., Kluwer Academic Publishers, Boston, 91-014 (1989). The addition of lysophospholipids to normoxic myocardial tissue in vitro induces electrophysiological alterations that are similar to those observed in the ischemic heart in vivo Corr et al, Circ. Res, 55, 135-54 (1984).
Most importantly, lysophospholipid accumulation in the ischemic dog heart in vivo has been correlated with the frequency of cardiac arrhythmias, Kinnaird et al, Lipids, 23, 32-35 (1988). Furthermore, it is known that the carnitine acyltransferase 1 inhibitor, 2-[5-(4-chlorophenyl)-pentyl]-oxirane-2-carboxylate (POCA), prevents the onset of ventricular fibrillation and ventricular tachycardia and inhibits the accumulation of lysophospholipids (and long-chain aoyloarnitines) in the ischemic cat heart in vivo, Corr et al, J. Clin. Invest., 83, 927-36 (1989).
Accelerated phospholipid catabolism by PLA.sub.2 has also been implicated as a cause of infarct damage in the ischemic heart. In the ischemic heart, ATP levels decrease. Treatment of rat neonatal myocytes with the glycolytic inhibitor iodoacetate lowers the levels of ATP which results in the release of arachidonic acid and morphological alterations of the myocytes, Chien et al, J. Clin. Invest., 75, 1770-80 (1985). One PLA.sub.2 inhibitor (U26,384) prevented the release of arachidonic acid, phospholipid degradation, sarcolemmal membrane defects and the release of creatine kinase that was induced by the treatment of rat neonatal myocytes with iodoacetate, Sen et al, J. Clin. Invest., 82, 1333-38 (1988).
Therefore, inhibition of myocardial PLA.sub.2 activity, without inhibiting other mammalian PLA.sub.2 enzymes, to prevent the accumulation of arrhythmogenic lysophospholipids in an ischemic heart is a potential therapeutic approach for the prevention of arrhythmias, infarct damage and sudden death.